Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Radiation and chemotherapeutic agents are effective in the treatment of cancer in humans, particularly solid tumors. However, cancer cells that survive the initial treatment become resistant to subsequent treatment. This resistance to subsequent treatment is a major reason for the lack of better overall survival of these patients. Hypoxia is also known to play a major role in the outcome of cancer therapy. A vast majority of human solid tumors exhibit hypoxia. Unfortunately, hypoxic tumor cells are more resistant than normoxic tumor cells to radiation treatment and chemotherapy and these hypoxic cells are considered a significant contributor to disease relapse (see, e.g., Teicher et al. (1990) Cancer Res., 50:3339-3344; Grau and Overgaard (1988) Radiother. Oncol. 13:301-309). Several studies have demonstrated that the hypoxic cells of solid tumors also lack glucose.
Glucose deprived cancer cells that consist of both hypoxic and normoxic cancer cells are more resistant to chemotherapeutic agents (Cui et al. (2007) Cancer Res., 67:3345-55). Glucose depletion is common in most solid tumors due to higher metabolic activity and lack of perfusion due to disorganized vasculature. It is also believed to induce tolerance to stress. There is a recent upsurge of interest by several labs in understanding the impact of glucose deprivation on cancer cells since the overall steady state level of glucose is believed to be lower in solid tumors particularly in hypoxic tumors (Aronen et al. (2000) Clin. Cancer Res., 6:2189-200; Rajendran et al. (2004) Clin. Cancer Res., 10:2245-52; Schroeder et al. (2005) Cancer Res., 65:5163-71). It has been suggested that the decrease in glucose level may be due to higher metabolic activity of cancer cells (Schroeder et al. (2005) Cancer Res., 65:5163-71). Ischemic conditions caused by disorganized vasculature may also be responsible for the lower level of glucose in solid tumors (Schroeder et al. (2005) Cancer Res., 65:5163-71). Several recent studies have looked into the impact of glucose deprivation on cancer cells in vitro (Yun et al. (2005) J. Biol. Chem., 280: 9963-9972; Katol et al. (2002) Oncogene, 21: 6082-6090; Ryoo et al. (2006) Biol. Pharm. Bull., 29:817-820). These studies have indicated several molecular mechanisms may be involved in the survival of glucose deprived tumor cells. These studies have demonstrated the importance of targeting glucose depleted cancer cells since it induces survival molecules that enable them to survive and be less responsive to therapy in spite of lack of glucose.
Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the oxidative pentose phosphate cycle (OPPC). Glucose, a substrate for the OPPC, is required for OPPC mediated detoxification of oxidants/disulfides. Glucose is utilized as a substrate by oxidative pentose phosphate cycle to generate reductants. These reductants are utilized to maintain reduced glutathione homeostasis in mammalian cells when exposed to oxidants/disulfides. Glutathione is a tripeptide consisting of glycine, cysteine and glutamate. The reduced GSH is up to 100 folds higher than the oxidized GSH (GSSG) in mammalian cells under normal conditions. However, the oxidized GSH produced by oxidants/disulfides is detrimental to cancer cells.